Inhalation method with controlled cyclic activation

ABSTRACT

A method for performing an inhalation using a nebulizer includes filling a reservoir with a medication fluid or connecting a medication container to a designated connecting piece: connecting a nebulizer unit to a control unit and a mouthpiece, at least temporarily activating the nebulizer unit; atomizing the medication fluid into a fine particulate aerosol which is emitted into an aerosol chamber formed by the nebulizer unit and the mouthpiece during activation of the nebulizer unit; performing the inhalation, with a user enclosing the mouthpiece with the lips and during inhalation, drawing air from outside into the aerosol chamber, where the air mixes with the aerosol, and then passes further through the mouthpiece as an air stream and into the respiratory tract and, possibly into the user&#39;s lung; measuring a pressure within the aerosol chamber and/or a flow rate through the aerosol chamber or the mouthpiece using the control unit; activating the nebulizer unit with each breath on occurrence of at least one activation criterion detected using the control unit; and deactivating the nebulizer unit with fulfilment of at least one stop criterion, wherein from a degree of fulfilment of the at least one activation and/or stop criterion, a weighted average value is formed and the inhalation is started when the weighted average value exceeds a threshold value.

CROSS-REFERENCE TO RELATED APPLICATION

This application is continuation of U.S. patent application Ser. No.16/317,136, filed May 17, 2019, which is a Section 371 National StageApplication of International Application No. PCT/DE2017/100581, filedJul. 13, 2017, the content of which is incorporated herein by referencein its entirety, and published as WO 2018/010733 on Jan. 18, 2018, notin English.

FIELD

Embodiments of the present disclosure relate to methods for performinginhalation using a nebulizer, and a nebulizer suitable for performingthe method.

BACKGROUND

In the case of diseases of the respiratory tract, in particular of thelarynx, bronchial tubes, alveolae or else the air sacs themselves, aninhalation therapy is often the most efficient and, most importantly,the most effective method for administering a medication to the desiredplace of action. For performing such inhalation therapy, so-callednebulizers are used today, in which a medication formulation, which ispresent in liquid form, is atomized by means of an atomizing unit toform a fine-particulate aerosol. The droplet size to be reached, here,depends on at which point in the respiratory tract the medication oughtto be deposited. In the case of diseases of the bronchial tubes, largerdroplet diameters are permissible or necessary compared to diseases ofthe air sacs, which can only be reached by the droplets of the aerosolif the droplet radius lies within the range of a few micrometers.

The atomization unit used in modern nebulizers usually consists of aso-called mesh-membrane, that is to say a fine metal membrane withmicroscopically small, funnel-shaped holes in a central region of themembrane, which usually has a circular outline, and a vibrationgenerator that is mechanically coupled to the membrane and sets it intorapid vibrations typically lying in the ultrasonic range. The medicationfluid is usually enclosed in a medication reservoir that is integratedin the nebulizer unit and is in direct contact with the atomization unitor the mesh membrane, so that on oscillation of the membrane, medicationliquid is forced through the funnel-shaped perforations of the membraneand an aerosol in the form of a fine-particulate mist is generated atthe outlet end of the membrane.

In the nebulizers that are usually used today, there is the disadvantagethat the atomization of the medication fluid takes place continuouslyvia the entire duration of the inhalation process, that is to say bothwhile the patient inhales and exhales. During the exhalation process,however, no medication can naturally pass into the lungs, as a result ofwhich the medication atomized at this time precipitates in themouthpiece at the outlet end of the atomization unit and is thus lostunused. A collection and reuse of this deposit is precluded because ofhygienic concerns, since the space at the outlet end of the aerosolgenerator is non-sterile.

To avoid these losses, it would thus be desirable if the atomizationprocess only took place during the inhalation process. Such a controlledatomization is known from the prior art for artificial respirators,which are used as stationary, relatively complex and expensive devicesin hospitals for ventilation of patients in intensive care units. Insuch machines, a detailed monitoring of the respiration cycle, includingmonitoring of the pressure and/or flow, takes place, resulting in acorresponding control of a nebulizer that is connected for controlpurposes to such an artificial respirator.

In the case of mobile, that is to say portable, nebulizers, a triggeringor other control is not known in general. That is to say, such devicescontinually atomize the medication fluid during an inhalation with theabove-described disadvantageous consequences. This is because the sensordevice associated with a monitoring of the respiration course would makethe device very complex and therefore also expensive.

One possibility of performing a controlled activation of the atomizationprocess, which is also suitable for portable units because of itsrelatively simple implementation is described in the patent document EP1 304 131 Bl. Here, it is taught that an output signal of theatomization device itself, that is to say of the vibration generator,which is mechanically coupled to the mesh membrane and comprises anelectromechanical piezocrystal, can be used to start the atomizationprocess. The disadvantage of this is that this output signal of thepressure change which acts on the membrane varies as a result of thestarting respiration process, and thus also responds sensitively toshocks of the inhaler. This is particularly disadvantageous in the caseof portable, hand-held inhalers, since these shocks take placeirregularly and unpredictably. The progress of the breathing operationcan therefore only take place approximately with the aid of this outputsignal.

SUMMARY

Embodiments of the present disclosure relate to a method for performinginhalation using a nebulizer and a nebulizer for performing the method.In one embodiment of the method, a reservoir is filled with a medicationfluid into a reservoir or connecting a medication container to adesignated connecting piece, possibly connecting a nebulizer unit to acontrol unit and/or mounting a mouthpiece, at least temporarilyactivating the nebulizer unit, during the activation, the medicationfluid being atomized into a fine particulate aerosol which is emittedinto an aerosol chamber which is formed by the nebulizer unit andmouthpiece, performing the inhalation, the user enclosing the mouthpiecewith the lips and during inhalation, drawing air from outside into theaerosol chamber, where the air mixes with the aerosol, and then passesfurther through the mouthpiece into the respiratory tract and, possiblyinto the lung of the user. The invention further describes a nebulizersuitable for performing the method.

One object of the present invention is therefore to find a process forperforming an inhalation and to develop a nebulizer, which is suitablefor performing this method and permits a most efficient and effectiveuse of medication, even when the nebulizer has a portable design.

In some embodiments, this object is achieved by a method for inhalationand a nebulizer for performing this method according to the independentclaims.

One embodiment of the nebulizer is designed such that, on the nebulizerunit, which contains the mesh membrane with the piezo vibrationgenerator coupled thereto has, as aerosol generator, an air channel,which, at one end, opens into the interior of the nebulizer unit in theaerosol unit, which is disposed in the outlet end of the aerosolgenerator, and at its second end, is led out of the nebulizer unit andcan be connected to the control unit. By this means, it is achievedthat, in the control unit, a suitable sensor for measuring a pressureand/or a flow through the mouthpiece can be installed, which is in fluidcommunication with the interior of the nebulizer unit.

The advantage of a nebulizer designed in this way is that the first endof the nebulizer can open at a most suitable point in the interior ofthe nebulizer unit at the outlet end of the aerosol generator, at whicha pressure difference during the course of the respiratory process ismaximum. The sensor, which is specifically used in the control unit, formonitoring the pressure and/or flow through the mouthpiece can then beselected within a certain scope. An optimization regarding differentcriteria can take place. On one hand, a most technically simple solutioncould be realized, in which a simple pressure sensor is used, whichresponds to a change of the total pressure.

This consists of a sum of the static and dynamic pressure. In the courseof a breath, the former is first depressed, whereupon, due to theaerosol chamber and the mouthpiece, an air stream transporting away theaerosol forms, which is reflected in a reduced dynamic pressure. If onlyone or other component is to be measured, a design similar to a Pitot'stube, used for velocity measurement in aircraft, could be implemented,which permits an automatic differential pressure formation. For thepurposes of aerosol production control, however, a measurement of thetotal pressure is sufficient in practice.

If a direct stream or flow measurement is desired, a heated resistor canbe used and the temperature change due to the air stream through theflow channel can be measured, or a miniaturized impeller can be used,which is operated by the air stream and the speed of which isproportional to the flow rate.

Since the accuracy of measurement of such a dedicated external sensor ishigher than that of one seated within the nebulizer unit, in particularif the output signal of the aerosol generator itself is interpreted as asensor signal and indicator of the suction pressure, it is possible toachieve a control of the aerosol production that is better adapted tothe respiratory profile.

The method according to some embodiments of the present disclosure forperforming an inhalation now provides that a nebulizer, which has apressure and/or flow-rate sensor, is actuated such that theatomization/aerosol production is started as soon as a start criterionis met, and is stopped when a stop criterion is reached.

The possible start criteria can be chosen depending on the sensitivityand possibilities of the sensor, and include: activation on exceedingthe threshold of the flow rate (air volume per unit time), activation onfalling below a threshold pressure, activation on reaching a particulartotal flow rate (volume) or activation on exceeding a threshold valuefor a target attainment probability, which is dynamically calculated bythe control unit using the respiratory profile previously measured. Inthe simplest case, the activation takes place in the form of atriggering, in which the inhalation is switched from completely off (0%aerosol production) to completely on (100% of maximum aerosol productionrate). Instead of a simple triggering, slow or continuous increase ofthe emitted aerosol amount can be provided, for example according to theformula:

$\frac{\overset{.}{m}}{{\overset{.}{m}}_{\max}} = {{Min}\lbrack {1,{{Max}{{0\frac{X - X_{1}}{X_{1} - X_{2}}}}}} \rbrack}$

Here, {dot over (m)} denotes the current and {dot over (m)}_(max), themaximum aerosol production rate (mass per time) and X or X₁, X₂, thecurrent value or threshold values of the control parameter (pressure,flow rate, flow quantity or target attainment probability) that is usedin each case.

The stop criteria, at which the aerosol generation, that is to say theatomization, is terminated, may comprise: expiry of a predetermined timespan, falling below a second threshold value for the flow rate and/orexceeding a second threshold value for the pressure and/or reaching asecond threshold value for the total flow rate and/or exceeding a secondthreshold value for the probability that an aerosol particle emitted atthat moment reaches its target in the respiratory tracts of the user.

The threshold values for activation and deactivation could also beselected to be identical, however, in practice, this is not usuallyuseful, since one usually wants to perform the activation as early aspossible with each breath and therefore chooses threshold values thatare as close as possible to the equilibrium value (without respiration).On the other hand, the switching off/deactivation of production shouldif possible take place when the air passing through the aerosol chamberat that moment would probably no longer pass into the target area,which, in view of the finite dead volume in the mouthpiece, mouth cavityand, possibly, a tube connecting nebulizer unit and mouthpiece, isusually the case significantly before the threshold value used foractivation is reached (again).

Concerning the type of disconnection, it is usually conceivable that,besides a simple, immediate switching off (stop triggering), acontinuous reduction of the aerosol production to zero takes place, forexample, as with the activation above, the aerosol production rate ischosen proportional to the standardized difference of a controlparameter and a threshold value. However, other, non-proportional,profiles can be provided.

The advantages of the method according to some embodiments of thepresent disclosure are diverse. On one hand, in a simple embodiment, astraightforward triggering can take place, which functions very simplyand reliably, specifically with the aid of a registered pressure or flowvalue. The essential advantage is that aerosol production does not takeplace if an aerosol particle probably does not reach its target, that isto say in particular during the exhalation process. By this means, themethod according to some embodiments of the present disclosure forperforming the inhalation ensures that, in a simple manner and withsimple means, since it only requires a single sensor, ensures thataerosol production only takes place when it is required, that is to saywhen the medication can be effective.

The advantageous consequences of this are first that, at the outlet endof the aerosol generator in the nebulizer unit, as well as in themouthpiece, no condensate from medication fluid that has not beenexhaled and is deposited on the walls, forms, which reduces the need forcleaning and is more hygienic overall. On the other hand, the density ofthe aerosol mist is reduced at the beginning of the inhalation process,which reduces the tendency for the user to suffer an irritation of thethroat, which might interrupt the inhalation for some time and, due topremature removal of the medication, also reduce the effect of theinhalation or compromise it altogether. A tendency to irritation of thethroat can advantageously be further reduced if, when the activation,that is to say the start criterion is reached, no simple triggering ofaerosol production takes place, but the production, as described above,is continuously increased to the maximum value.

Since aerosol production only takes place when it is required, expensivemedication is advantageously saved, and thereby the costs of a therapyadvantageously significantly reduced. The beginning of aerosolproduction, and its termination, that is to say the deactivation ispossible either before execution of the inhalation or else dynamicallyduring the inhalation due to the measured actual pressure or flowconditions. Herein, the start as well as the stop criteria that are usedcan be adapted, that is to say the threshold values for pressure and/orflow rate, or the total flow rate determined to that point or the targetattainment probability are increased or reduced. If necessary, the ratecan also be changed, in which the aerosol generation after a triggeringis increased and/or reduced to the maximum value. With a simpleimmediate termination of aerosol production after expiry of a time span,the aerosol production can also be determined in advance or dynamicallyadapted. The control takes place in all cases via the control unit ofthe nebulizer according to some embodiments of the present disclosure,in which either the user manually sets his desired parameters or thecontrol unit allows an automatic, dynamic adjustment to be performed.

A further advantage, which cannot be neglected in the case of portablenebulizers consists in the fact that, due to the more efficient, onlytemporary activation of aerosol production, the battery of the device ispreserved.

Further advantageous embodiments of the present disclosure, which can berealized individually or in combination, in so far as they do notobviously preclude one another are described below.

Some embodiments of the present disclosure propose that, in the courseof monitoring the respiration profile from the control unit, anintegration of the measured flow rate takes place, so that the inhaledair quantity, that is to say the respiratory volume, is also known. Thiscan then also be used for activation as well as for deactivation ofaerosol production, wherein, for example, an activation takes place whena certain first threshold value is exceeded and the deactivation takesplace when a certain second threshold value is exceeded.

Alternatively, in the control unit, an approximate target attainmentprobability can be computed, which indicates how probable it is that anaerosol particle produced at a certain time arrives at its targetlocation in the respiratory tracts of the user. This probability takesin to account, on one hand, the target location to be reached, that isto say whether the aerosol in the bronchial tubes, the alveolae or airsacs is to be deposited and on the other hand on the residualrespiratory volume still remaining. Herein, it is advantageous if theentire volume of a breath is known. This can either be measured inadvance by other means and the measured value be stored in the controlunit, or it is determined by the nebulizer according to some embodimentsof the present disclosure during the inhalation itself and, in certaincircumstances, also dynamically adapted to a changing respiratorybehaviour of the user.

As criterion for starting aerosol production, the following come intoconsideration: exceeding a threshold value of the flow, falling below athreshold value of the pressure, exceeding a total flow rate, exceedinga threshold value for the target attainment probability. As stopcriteria, the following come into consideration: expiry of a time spansince the activation of aerosol production, falling below a secondthreshold value of the flow rate, exceeding a second threshold value ofthe pressure, exceeding a second threshold value of the total flow rate,and/or falling below a second threshold value of the target attainmentprobability. Herein, the used first and second threshold values can alsobe identical. It should be emphasised that some embodiments of thepresent disclosure provide that the start and stop criteria can bearbitrarily combined with one another, that is to say it for starting,that is to say for activating aerosol production, for example theexceeding of a threshold value of the flow rate for completing aerosolproduction, but the reaching of a certain threshold value of the totalflow rate can be used.

All threshold values can be preset and unchangeable, or chosen by theuser himself before inhalation. In addition, it is conceivable that thecontrol unit performs a dynamic adaptation to actually measured values.If, for example, it is ascertained that a total flow rate, that is tosay respiratory volume always lies below a threshold value, this can bereduced. If, on the other hand, the respiratory volume liessignificantly above the threshold value, this can be increased toutilize a larger proportion of the inhalation phase.

Threshold values can also be used in combination, that is to say thecontrol unit simultaneously monitors multiple criteria and starts orstops aerosol production because of the occurrence of all or at leastone criterion. This is in particular appropriate when a total flowrate/respiratory volume is used as stop criterion. To avoid thenon-reaching of the deactivation threshold value, e.g. the continuationof aerosol production due to shallow breathing or a small lung volume,the disconnection may additionally take place after expiry of a timespan.

As generalization, some embodiments of the present disclosure proposethat the control unit determines a degree of fulfilment, that is to saya percentage value, for each criterion, which, depending on the natureof the control parameter and the process (activation/deactivation), inthe simplest case

These degrees of fulfilment can then be calculated by the control unitwith weighting factors on the part of the user or else fixedpredetermined or else adaptable in the course of inhalation to form aweighted average degree of fulfilment. Activation or deactivation ofaerosol production then takes place in such a method when the degree offulfilment of the first and second threshold values are reached.

The pressure measurement then preferably takes place by means of apressure sensor in the control unit, which, due to the flow channel ofthe nebulizer being in fluid communication with the outlet end of theaerosol generator, so that the pressure changes there can be registeredby the sensor within the control unit. Alternatively, a direct flowmeasurement may also take place, either in that the back pressure of theair stream through the flow channel is measured or in that a temperaturemeasurement of a reference resistance takes place, or in that therotational speed of an impeller operated by the flow in the flow channelis measured. In this case, the control device would need to have an airinlet, which is in fluid communication with the flow channel.

Further details and features of embodiments of the present disclosureare described below with reference to the figures of preferred exemplaryembodiments described in greater detail. These are only intended toillustrate the various embodiments, and in no way to limit them.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a longitudinal section through the nebulizer unit, withmounted mouthpiece, of a preferred embodiment of the nebulizer accordingto the invention with flow channel; and

FIG. 2 shows exemplary graphs for flow rate and aerosol production inthe course of time in the case of inhalation controlled according to themethod according to the invention.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

FIG. 1 shows a longitudinal section through the nebulizer unit 1 withmounted mouthpiece of an embodiment of a nebulizer with flow channelaccording to embodiments of the present disclosure. The centerpiece ofthe nebulizer unit 1 is formed by the aerosol generator 101, which ismechanically retained by the sealing ring 102 and retaining structure103. At the input end of the aerosol generator 101, the medicationreservoir 11, which can be firmly sealed by a cap 13, can be seen, intowhich the liquid medication is filled. At the outlet end of the aerosolgenerator 101, there lies the aerosol chamber 120, an essentiallycylindrical volume, in which the medication mist collects afteratomization, before it is transported away through the mouthpiece 2 withthe air stream generated by the user. The mouthpiece 2, for easiercleaning, is designed so as to be removable and in operation is pluggedon a connecting piece 12, which is present on the nebulizer unit 1.

On the underside of the nebulizer unit, the flow channel 104 can beseen, which opens with its front end in the aerosol chamber 102, locatedin the outlet end of the aerosol generator 101, and with its second endis guided rearward, where it ends in a truncated conical nozzle, whichcan be connected to the control unit.

The opening of the flow channel 104 forms the reference point of thepressure measurement. It lies within that portion of the aerosol chamber120 that is located in the mouthpiece 2, which has the decisiveadvantage that the measurable total pressure change is higher than thatat a measurement point further in the direction of the aerosol generator101. On one hand the respiratory cycle of the user can thus be moreaccurately monitored, on the other hand the pressure that is picked upthere is also hardly influenced by shocks or general movements of thenebulizer, which advantageously further increases the accuracy.

FIG. 2 shows two graphs as an example of a time profile of flow rate{dot over (V)} for two inhalation operations (top graph) as well asthree different aerosol production rates {dot over (m)}₁, {dot over(m)}₂, {dot over (m)}₃, which are controlled according to embodiments ofthe present disclosure (lower graph).

As can be seen, with a first actuation process, dotted curve {dot over(m)}₁, the full aerosol production is triggered as soon as a thresholdvalue {dot over (V)}₁ of the flow is exceeded, and stopped when it fallsbelow a second threshold value {dot over (V)}₂.

The second aerosol production according to embodiments of the presentdisclosure, presented as a continuous line {dot over (m)}₂, provides,before the first threshold value {dot over (V)}₁ is reached, anactivation with reduced production rate, which then, towards a thresholdvalue {dot over (V)}₃, is increased to a maximum value, before, onfalling below this threshold value {dot over (V)}₃, a reduction of theaerosol production starts, and this is eventually completely deactivatedwhen the threshold value {dot over (V)}₂ is reached and fallen below.

As third, preferred mode of actuation, which is perhaps simplest torealize, dotted curve {dot over (m)}₃, embodiments of the presentdisclosure provide provides, after triggering on reaching the flowthreshold value {dot over (V)}₁ to make the deactivation dependent onthe expiry of a time span T.

LIST OF REFERENCE CHARACTERS

-   1 Nebulizer unit-   11 Medication reservoir-   12 Connecting piece for mouthpiece 2-   13 Cap-   101 Aerosol generator-   102 Sealing ring-   103 Retaining structure-   104 Flow channel for connection to control unit-   2 Mouthpiece-   21 Aerosol chamber-   {dot over (V)} Flow rate-   {dot over (V)}₁ First threshold value of the flow rate-   {dot over (V)}₂ Second threshold value of the flow rate-   {dot over (V)}₃ Third threshold value of the flow rate-   {dot over (m)}₁ First aerosol production rate-   {dot over (m)}₂ Second aerosol production rate-   {dot over (m)}₃ Third aerosol production rate-   T Time span

Although the embodiments of the present disclosure have been describedwith reference to preferred embodiments, workers skilled in the art willrecognize that changes may be made in form and detail without departingfrom the spirit and scope of the present disclosure.

1-14. (canceled)
 15. A method for performing an inhalation using anebulizer, comprising: filling a reservoir with a medication fluid orconnecting a medication container to a designated connecting piece;connecting a nebulizer unit to a control unit and a mouthpiece, at leasttemporarily activating the nebulizer unit; atomizing the medicationfluid into a fine particulate aerosol which is emitted into an aerosolchamber formed by the nebulizer unit and the mouthpiece duringactivation of the nebulizer unit; performing the inhalation, with a userenclosing the mouthpiece with the lips and during inhalation, drawingair from outside into the aerosol chamber, where the air mixes with theaerosol, and then passes further through the mouthpiece as an air streamand into the respiratory tract and, possibly into the user's lung;measuring a pressure within the aerosol chamber and/or a flow ratethrough the aerosol chamber or the mouthpiece using the control unit;activating the nebulizer unit with each breath on occurrence of at leastone activation criterion detected using the control unit; anddeactivating the nebulizer unit with fulfilment of at least one stopcriterion, wherein from a degree of fulfilment of the at least oneactivation and/or stop criterion, a weighted average value is formed andthe inhalation is started when the weighted average value exceeds athreshold value.
 16. The method according to claim 15, wherein anatomization rate is controlled depending on the difference between thepressure and/or the flow rate and a threshold value for the pressureand/or the flow rate.
 17. The method according to claim 15, furthercomprising calculating a total flow rate including integrating themeasured flow rate over time using the control unit.
 18. The methodaccording to claim 15, further comprising calculating a targetattainment probability for each breath of a user using the control unit.19. The method according to claim 15, wherein the at least one stopcriterion comprises one or more of: an expiration of a time span; thepressure exceeding a threshold pressure; the flow rate falling below athreshold flow rate; the flow rate reaching a preset total flow rate;and calculating a target attainment probability for a breath of the userusing the control unit that falls below a precalculated targetattainment probability.
 20. The method according to claim 15, whereinweighting factors used in calculating the weighted average value areadapted in the course of the inhalation.
 21. The method according toclaim 15, wherein, stop criteria specified at the start of inhalation,in particular the expiry of a time span, are more strongly weighted andthis weighting is changed in the course of inhalation in favour ofuser-modified stop criteria, in particular reaching a total flow rate orfalling below a target attainment probability.
 22. The method accordingto claim 15, wherein: measuring the pressure comprises measuring thepressure using a pressure sensor of the nebulizer; and measuring theflow rate comprises measuring the flow rate using a flow rate sensor ofthe nebulizer.
 23. The method according to claim 15, wherein measuringthe flow rate comprises at least one of: measuring a dynamic pressure inthe mouthpiece or an air channel leading to the mouthpiece; measuring atemperature of a reference resistor exposed to the air stream; andmeasuring a rotational speed of an impeller driven by the air stream.24. The method according to claim 15, wherein the at least one stopcriterion includes a threshold value of a total flow rate that isadapted in the course of inhalation to total flow rate valuescorresponding to actual respiration volumes of the user.
 25. A nebulizerfor performing the method according to claim 15, comprising: a nebulizerunit including a medication reservoir; a control unit configured tocontrol the actuation of an aerosol generator enclosed in the nebulizerunit; a mouthpiece for mounting on a connecting piece of the nebulizerunit; and an aerosol chamber, which is delimited at its circumference bythe connecting piece and the mouthpiece as well as at its end by theaerosol generator, wherein the nebulizer unit includes an air channelhaving a first end that is connected to an outlet end of the aerosolgenerator in the aerosol chamber, and a second end that is connected tothe control unit.